Congenital primary aphakia

Summary

Congenital primary aphakia (MONDO:0012456) is a disease caused by FOXE3 (GenCC Definitive), with 3 cohort genes and 1 clinical trial. Top therapeutic interventions include amphotericin b and sodium chloride.

At a glance

• Prevalence: 1-5 / 10 000 (Europe)
• Causal gene: FOXE3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 415
• Phenotypes (HPO): 13
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000568	Microphthalmia	Very frequent (80-99%)
HP:0001087	Developmental glaucoma	Very frequent (80-99%)
HP:0007707	Congenital aphakia	Very frequent (80-99%)
HP:0008062	Aplasia/Hypoplasia affecting the anterior segment of the eye	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0000541	Retinal detachment	Frequent (30-79%)
HP:0000588	Optic disc coloboma	Frequent (30-79%)
HP:0000647	Sclerocornea	Frequent (30-79%)
HP:0007973	Retinal dysplasia	Frequent (30-79%)
HP:0011483	Anterior synechiae of the anterior chamber	Frequent (30-79%)
HP:0000526	Aniridia	Occasional (5-29%)
HP:0000667	Phthisis bulbi	Occasional (5-29%)
HP:0100583	Corneal perforation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital primary aphakia
Mondo ID	MONDO:0012456
MeSH	C537786
OMIM	610256
Orphanet	83461
DOID	DOID:0080607, DOID:11367
ICD-10-CM	Q12.3
ICD-11	885383581
NCIT	C35172
SNOMED CT	35387008
UMLS	C1853230
MedGen	339935
GARD	0009952
MedDRA	10002947
Is cancer (heuristic)	no

Also known as: anterior segment dysgenesis 2, multiple subtypes · aphakia, congenital primary · ASGD2 · congenital absence of lens · congenital aphakia · CPA

Data availability: 415 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › lens disorder › congenital primary aphakia

Related subtypes (9): lens subluxation, posterior dislocation of lens, cataract, blepharoptosis-myopia-ectopia lentis syndrome, classic homocystinuria, facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome, ectopia lentis-chorioretinal dystrophy-myopia syndrome, isolated ectopia lentis, encephalopathy due to sulfite oxidase deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

415 retrieved; paginated sample, class counts are floors:

263 uncertain significance, 84 likely benign, 26 conflicting classifications of pathogenicity, 17 pathogenic, 12 benign/likely benign, 6 likely pathogenic, 4 benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1077103	NM_012186.3(FOXE3):c.21_24del (p.Met7fs)	FOXE3	Pathogenic	criteria provided, single submitter
1428067	NM_012186.3(FOXE3):c.555dup (p.Phe186fs)	FOXE3	Pathogenic	criteria provided, single submitter
2947078	NM_012186.3(FOXE3):c.706G>T (p.Glu236Ter)	FOXE3	Pathogenic	criteria provided, single submitter
4783515	NM_012186.3(FOXE3):c.472G>C (p.Gly158Arg)	FOXE3	Pathogenic	criteria provided, single submitter
8448	NM_012186.3(FOXE3):c.720C>A (p.Cys240Ter)	FOXE3	Pathogenic	criteria provided, multiple submitters, no conflicts
1077104	NM_012186.3(FOXE3):c.148_170dup (p.Gly58fs)	LINC01389	Pathogenic	no assertion criteria provided
1077106	NM_012186.3(FOXE3):c.543del (p.Pro182fs)	LINC01389	Pathogenic	no assertion criteria provided
1418123	NM_012186.3(FOXE3):c.632C>A (p.Ser211Ter)	LINC01389	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459316	NM_012186.3(FOXE3):c.343_347del (p.Trp115fs)	LINC01389	Pathogenic	criteria provided, single submitter
2086066	NM_012186.3(FOXE3):c.145G>T (p.Gly49Ter)	LINC01389	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2118980	NM_012186.3(FOXE3):c.393_419delinsCGGCCAGTGCTCCTTTATCCATGGGAGCTGGGAATAATCCCAGAGAGCAGACAACCTGCTGCTCAGATACATTCACACAAGTGTGTACACACACATGCCCAGCCCATCTCGTCTCTACCAGGCTGAGATGCAGGAGATGGCATTTGACTAGGCCTACTATGTGCACAGCTATGGCTGAATCACTTCCTTTTTAAAACAAAATTGTGTTAGCCACTAATCCTGCTGGAGAATCACTTCCTAATCCCATTTCATGAACTTCTGATTGATGTCTCACAAGGAGGTTCACCC (p.Lys131_Gly140delinsAsnGlyGlnCysSerPheIleHisGlySerTrpGluTer)	LINC01389	Pathogenic	criteria provided, single submitter
2922450	NM_012186.3(FOXE3):c.535del (p.Ala179fs)	LINC01389	Pathogenic	criteria provided, single submitter
2922986	NM_012186.3(FOXE3):c.705del (p.Glu236fs)	LINC01389	Pathogenic	criteria provided, single submitter
2952039	NM_012186.3(FOXE3):c.222C>G (p.Tyr74Ter)	LINC01389	Pathogenic	criteria provided, single submitter
30157	NM_012186.3(FOXE3):c.959G>T (p.Ter320Leu)	LINC01389	Pathogenic	no assertion criteria provided
3237156	NM_012186.3(FOXE3):c.873dup (p.Pro292fs)	LINC01389	Pathogenic	criteria provided, single submitter
3756762	NM_012186.3(FOXE3):c.56_59del (p.Leu19fs)	LINC01389	Pathogenic	criteria provided, single submitter
427852	NM_012186.3(FOXE3):c.232G>A (p.Ala78Thr)	LINC01389	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8447	NM_012186.3(FOXE3):c.942dup (p.Leu315fs)	LINC01389	Pathogenic	no assertion criteria provided
935371	NM_012186.3(FOXE3):c.291C>G (p.Ile97Met)	LINC01389	Pathogenic	criteria provided, single submitter
1077105	NM_012186.3(FOXE3):c.286G>A (p.Ala96Thr)	FOXE3	Likely pathogenic	no assertion criteria provided
1424381	NM_012186.3(FOXE3):c.387C>G (p.Phe129Leu)	FOXE3	Likely pathogenic	criteria provided, single submitter
983475	NM_012186.3(FOXE3):c.289A>G (p.Ile97Val)	FOXE3	Likely pathogenic	criteria provided, single submitter
1077107	NM_012186.3(FOXE3):c.359G>C (p.Arg120Pro)	LINC01389	Likely pathogenic	no assertion criteria provided
1710250	NM_012186.3(FOXE3):c.388G>T (p.Val130Phe)	LINC01389	Likely pathogenic	no assertion criteria provided
839342	NM_012186.3(FOXE3):c.181del (p.Arg61fs)	LINC01389	Likely pathogenic	criteria provided, single submitter
1004513	NM_012186.3(FOXE3):c.166G>A (p.Ala56Thr)	FOXE3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1747161	NM_012186.3(FOXE3):c.537G>T (p.Ala179=)	FOXE3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1764790	NM_012186.3(FOXE3):c.882C>A (p.Ala294=)	FOXE3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2448358	NM_012186.3(FOXE3):c.363C>T (p.His121=)	FOXE3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FOXE3	Definitive	Autosomal dominant	congenital primary aphakia	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXE3	Orphanet:708	Peters anomaly
FOXE3	Orphanet:83461	Congenital primary aphakia
FOXE3	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXE3	HGNC:3808	ENSG00000186790	Q13461	Forkhead box protein E3	gencc,clinvar
CMPK1	HGNC:18170	ENSG00000162368	P30085	UMP-CMP kinase	clinvar
LINC01389	HGNC:50661	ENSG00000225762		long intergenic non-protein coding RNA 1389	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXE3	Forkhead box protein E3	Transcription factor that controls lens epithelial cell growth through regulation of proliferation, apoptosis and cell cycle.
CMPK1	UMP-CMP kinase	Catalyzes the phosphorylation of pyrimidine nucleoside monophosphates at the expense of ATP.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	9.2×	0.313
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXE3	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
CMPK1	Kinase	yes	2.7.4.14	Adenylat/UMP-CMP_kin, UMP_CMP_kinase, P-loop_NTPase
LINC01389	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
mucosa of transverse colon	2
primordial germ cell in gonad	2
jejunal mucosa	1
palpebral conjunctiva	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXE3	36	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon
CMPK1	288	ubiquitous	marker	jejunal mucosa, palpebral conjunctiva, parotid gland
LINC01389	130	broad	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CMPK1	3,432
FOXE3	1,003
LINC01389	0

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CMPK1	P30085	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FOXE3	Q13461	66.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interconversion of nucleotide di- and triphosphates	1	356.9×	0.005	CMPK1
Metabolism of nucleotides	1	300.5×	0.005	CMPK1
Metabolism	1	11.6×	0.086	CMPK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
trabecular meshwork development	1	4213.0×	0.002	FOXE3
CDP biosynthetic process	1	4213.0×	0.002	CMPK1
positive regulation of lens epithelial cell proliferation	1	4213.0×	0.002	FOXE3
pyrimidine ribonucleotide biosynthetic process	1	2808.7×	0.002	CMPK1
ciliary body morphogenesis	1	2106.5×	0.002	FOXE3
UDP biosynthetic process	1	1685.2×	0.002	CMPK1
‘de novo’ pyrimidine nucleobase biosynthetic process	1	1404.3×	0.002	CMPK1
negative regulation of lens fiber cell differentiation	1	1404.3×	0.002	FOXE3
iris morphogenesis	1	936.2×	0.003	FOXE3
nucleobase-containing small molecule interconversion	1	842.6×	0.003	CMPK1
cornea development in camera-type eye	1	648.1×	0.003	FOXE3
cell development	1	443.5×	0.004	FOXE3
lens development in camera-type eye	1	187.2×	0.009	FOXE3
eye development	1	175.5×	0.009	FOXE3
mRNA transcription by RNA polymerase II	1	165.2×	0.009	FOXE3
epithelial cell proliferation	1	156.0×	0.009	FOXE3
anatomical structure morphogenesis	1	69.6×	0.019	FOXE3
regulation of cell cycle	1	37.3×	0.033	FOXE3
transcription by RNA polymerase II	1	35.3×	0.033	FOXE3
negative regulation of apoptotic process	1	17.4×	0.062	FOXE3
cell differentiation	1	14.6×	0.071	FOXE3
regulation of transcription by RNA polymerase II	1	5.8×	0.164	FOXE3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CMPK1	2	3
FOXE3	0	0
LINC01389	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CRENOLANIB	3	CMPK1
LINIFANIB	3	CMPK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CMPK1	12	Binding:11, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CMPK1	2.7.4.14	UMP/CMP kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CRENOLANIB	3	CMPK1
LINIFANIB	3	CMPK1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	CMPK1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FOXE3, LINC01389

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXE3	0	—
LINC01389	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06447402	PHASE3	RECRUITING	A Trial to Compare Nebulized Amphotericin B and Nebulized Normal Saline as Maintenance in Patients With Chronic Pulmonary Aspergillosis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AMPHOTERICIN B	4	1
SODIUM CHLORIDE	4	1
CHEMBL6067678	0	1